Individuals suffering from mental illnesses and drug dependence are at greater risk for infection by human immunodeficiency virus (HIV) than the general population. Furthermore, moderate levels of adherence to antiretroviral therapy (ART) regimens by these individuals promotes the evolution of drug resistant viruses, limiting the effectiveness of ART in this population. The work described in this proposal will examine the biological consequences for HIV of resistance to the protease inhibitor (PI) class of ART. Specifically, the fitness, resistance, and virion composition of a spectrum of resistance genotypes, from those bearing single resistance-associated mutations to complex clinically derived pro sequences, will be examined using highly sensitive assays. The information from these studies will contribute to both basic and clinical understanding of HIV by: i) determining the mechanisms of PI resistance and virus fitness changes by different classes of resistance-associated mutations; ii) identifying the mechanisms of increasing drug resistance in increasingly Complex resistance genotypes; and iii) examining the molecular events associated with loss of virus fitness. Ultimately, these studies will impact clinical HIV treatment by improving the prediction of responses to ART.